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Reducing the Adverse Impacts of Substance Abuse

Neurobiology reveals the way to new treatments, but slowly.

The treatment of substance use disorders potentially affects not only the patient, but also society at large. This past year, studies suggested that substance abuse accounts for most of the putative link between mental illness and violence (JW Psychiatry Mar 16 and May 22) and increases the risk for acquaintance violence, whether the substance abuser is perpetrator or victim. Substance abuse also worsens outcomes (e.g., risk for rehospitalization) in patients with mood disorders.

Coincident with our improved understanding of the effects of substance abuse and dependence, we have greater appreciation of its strong neurobiological underpinnings. Elegant studies have demonstrated that chronic substance use causes progressive changes in gene expression in the brain (Clin Neuropharmacol 32:269). Addiction essentially "rewires" the brain, causing changes in executive function, reward salience, and impulsivity that drive continued use.

In 2009, researchers continued to search for medications that act on neurobiological systems to improve rates of recovery and abstinence. One candidate is prazosin, an alpha-1 noradrenergic receptor blocker that reduces noradrenergic outflow in the frontal lobe and is used to treat nightmares in patients with post-traumatic stress disorder. In a small, placebo-controlled study, prazosin reduced drinking frequency in alcohol-dependent subjects. Naltrexone, a µ-opiate receptor antagonist approved for treating alcoholism, reduced amphetamine use and craving in amphetamine-dependent subjects in a randomized, controlled trial. This study also highlighted that various drugs of abuse have common underlying neural and molecular circuits — in this case, dopamine neurons that have colocalized opiate receptors. (Specific drugs of abuse also likely have unique molecular substrates.)

Hypothesizing that food and substance "addictions" affect mesolimbic "reward" systems similarly, scientists conducting basic research have identified potential new targets for addiction medication. The obesity-related peptide ghrelin increased alcohol intake in alcohol-habituated mice, and ghrelin antagonists reduced alcohol's rewarding effects. Other researchers identified a kinase growth-factor signaling pathway in fruit flies that controls sensitivity to alcohol effects; drugs that target this pathway might limit the rewarding effects of alcohol.

The need for new treatment approaches for the most serious drug addictions is pressing. A bold study from Canada compared the use of injectable heroin with methadone maintenance for heroin dependence and found the former more effective, although, not unexpectedly, less safe. This finding suggests that simply providing the drug of abuse in a protected setting could improve outcomes in heroin users, although this approach requires costly medical surveillance to reduce the medical morbidity and potential mortality associated with using heroin. In a randomized trial comparing surgically implanted sustained-release naltrexone and oral naltrexone for heroin dependence, implants were associated with better abstinence rates (63% vs. 26%) and with less return to regular use. With no approved pharmacotherapy for cocaine addiction, other investigators creatively examined a potential vaccine (Arch Gen Psychiatry 66:1116). After five vaccinations over 12 weeks, 38% of cocaine-dependent subjects developed adequate antibodies to cocaine; these subjects were more likely to have cocaine-free urine samples than placebo recipients (55% vs. 45%) and to have no cocaine use 50% of the time than vaccinated subjects without adequate antibodies (53% vs. 23%).

The new emphasis on neurobiological aspects of addiction has probably facilitated the marketing of a non–evidence-based combination (marketed as Prometa) of the anticonvulsant gabapentin with the benzodiazepine antagonist flumazanil for generic treatment of "addiction." In the first randomized, controlled test of this combination, it was more effective than placebo in promoting abstinence in alcohol-dependent patients, but only among patients with prominent alcohol withdrawal symptoms. A subsequent study documented the efficacy of gabapentin alone for alcohol withdrawal, which places into doubt the value that flumazanil adds to Prometa. Still, neurobiological evidence supports the use of flumazanil, with animal studies showing that it "resets" molecular changes usually associated with alcohol tolerance and withdrawal at the receptor level.

In the end, marketing and scientific spin are no substitutes for solid controlled data. Another study, which, ironically, focused on the use of gabapentin for unapproved indications, documents that results of some efficacy studies are selectively published and do not always include a priori outcomes. This finding reminds us to be judicious and meticulous in providing unapproved treatments to our patients, even if they are desperate for novel approaches to relieve their suffering.

— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry January 4, 2010